CN114173915A - Film and polymer for producing same - Google Patents
Film and polymer for producing same Download PDFInfo
- Publication number
- CN114173915A CN114173915A CN202080055421.8A CN202080055421A CN114173915A CN 114173915 A CN114173915 A CN 114173915A CN 202080055421 A CN202080055421 A CN 202080055421A CN 114173915 A CN114173915 A CN 114173915A
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- polymer
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- membrane
- copolymer
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
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- 238000003303 reheating Methods 0.000 description 1
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- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- B01D67/0006—Organic membrane manufacture by chemical reactions
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F283/00—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
- A61M1/1621—Constructional aspects thereof
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- B01D61/24—Dialysis ; Membrane extraction
- B01D61/243—Dialysis
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- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/24—Dialysis ; Membrane extraction
- B01D61/243—Dialysis
- B01D61/244—Dialysis comprising multiple dialysis steps
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- B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F226/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
- C08F226/06—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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- C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
- C08G81/024—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
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- C08L39/04—Homopolymers or copolymers of monomers containing heterocyclic rings having nitrogen as ring member
- C08L39/06—Homopolymers or copolymers of N-vinyl-pyrrolidones
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- C—CHEMISTRY; METALLURGY
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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- C—CHEMISTRY; METALLURGY
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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Abstract
The present invention relates to novel copolymers and their use in the manufacture of porous membranes for hemodialysis applications.
Description
Cross reference to related patent applications
This application claims priority to application number 62/883269 filed in the united states at 6.8.2019 and application number 19197990.5 filed in europe at 18.9.2019, the entire contents of which are incorporated herein by reference for all purposes.
Technical Field
The present invention relates to novel copolymers and their use in the manufacture of porous membranes for hemodialysis applications.
Background
Porous membranes are discrete, thin interfaces that slow the permeation of chemicals that come into contact with them. A key characteristic of porous membranes is their ability to control the permeation rate of chemical species through the membrane itself. This function is exploited in many different applications, like separation applications (water and gas) or biomedical applications, such as drug delivery applications and hemodialysis, i.e. extracorporeal processes where the uremic retentate is removed through a semi-permeable membrane to clean the blood.
Polymeric membranes suitable for use as microfiltration and ultrafiltration typically control permeation under a "sieve" mechanism, where the passage of liquid or gas is dominated by convective flux.
Such polymer membranes are made primarily by phase inversion processes, which can produce articles having a very large fraction of voids (porosity).
For this purpose, a homogeneous polymer solution (also referred to as "stock solution") comprising the polymer, a suitable solvent and/or co-solvent and optionally one or more additives is typically cast into a film and then precipitated by contacting it with a non-solvent medium by the so-called non-solvent induced phase separation (NIPS) method. The non-solvent medium is typically water or a mixture of water and surfactant, alcohol and/or solvent itself.
Precipitation can also be induced by lowering the temperature of the polymer solution by the so-called Thermally Induced Phase Separation (TIPS) method.
Alternatively, in the so-called vapor-induced phase separation (VIPS) method, precipitation may be induced by contacting a film obtained via casting with air having a very high water vapor content.
Nevertheless, the precipitation can be induced by evaporating the solvent from the thin film obtained through casting by a so-called Evaporation Induced Phase Separation (EIPS) method. Typically, low boiling organic solvents (such as tetrahydrofuran, acetone, methyl ethyl ketone, and the like) are used in this process in admixture with water (the so-called "non-solvent") for the preparation of the polymer solution. The polymer solution is first extruded and then precipitated as a result of evaporation of the volatile solvent and enrichment of the non-solvent.
The above methods may be used in combination and/or sequence to provide membranes having specific morphology and properties. For example, the EIPS method can be combined with the VIPS method and the NIPS method to complete the precipitation process.
Aromatic sulfone polymers are high performance polymers with high mechanical strength and high thermal stability; they are used in a variety of industrial applications, including the manufacture of microfiltration and ultrafiltration membranes, such as those used in the biomedical field. For example, microporous membranes for use in the manufacture of hemodialysis devices can be obtained by spinning from a stock solution (otherwise referred to as a "spinning solution") comprising a polymer, a solvent, a pore former, and a surface-modifying macromolecule, as disclosed, for example, in US 2011/009799 a (interfacial BIOLOGICS, INC.).
Despite the high mechanical strength and high thermal stability of the aromatic sulfone polymers currently used for the manufacture of microfiltration and ultrafiltration membranes, there is still a need to obtain improved materials for the manufacture of hemodialysis membranes.
Membranes prepared from a mixture obtained by mixing together at least one hydrophobic first polymer (e.g. polyamide) and a hydrophilic second polymer (e.g. polyvinylpyrrolidone), optionally with suitable additives, have been widely disclosed in the art (e.g. in EP 0305787, EP 2113298 and US 8,596,467).
However, the membranes obtained using said blends are not suitable for hemodialysis applications, since a release of hydrophilic polymers may occur, which leads to undesired health defects of the patient, such as for example severe allergic reactions.
EP 2253369(Gambro Lundia AB) discloses a permselective asymmetric membrane comprising a copolymer of vinylpyrrolidone and sulfobetaine, which copolymer comprises (meth) acrylic acid moieties.
WO 2013/034611(Gambro Lundia AB) discloses a semipermeable asymmetric hollow fiber membrane which is a graft copolymer of at least one hydrophobic polymer and at least one hydrophilic polymer. More specifically, the membrane is made of a graft copolymer of: at least one graft copolymer of polysulfone or polyethersulfone, preferably in an amount of from 90 to 99 wt.%, based on the total weight of the graft copolymer, and at least one polyvinylpyrrolidone, preferably in an amount of from 1 to 10 wt.%, based on the total weight of the graft copolymer.
The examples of this patent application show a content of chemically bound PVP of about 2.0 wt.% in the final copolymer. Without being bound by any theory, applicants believe that this low amount of PVP in the final copolymer is due to the mechanical process by which the final copolymer is obtained.
EP 3108955 (Pall Corporation) discloses a porous membrane comprising an aromatic hydrophobic polymer and a wetting agent comprising a copolymer having the formula a-B or a-B-a, wherein a is a hydrophilic segment comprising a polymeric monomer or mixture of monomers having the formula CH2 ═ C (R1) C (R2); and B is an aromatic hydrophobic polymer segment, wherein B and a are linked by an amidoalkylthio group represented by the formula: -B- [ NH-C (═ O) - (CH)2)a-S]-A-。
The synthesis disclosed in this patent begins with the reaction of a diamine macromer (i.e., a difunctional starting compound) with sodium thioglycolate to provide a macro-CTA (chain transfer agent) terminated at both of its chain ends with-SH groups, which is then reacted with 1-vinylpyrrolidin-2-one and Azobisisobutyronitrile (AIBN) to provide a block copolymer having the formula:
the aromatic hydrophobic polymer is selected from the group consisting of Polysulfone (PSU), polyphenylene ether sulfone (PPES), Polyethersulfone (PES), Polycarbonate (PC), Polyetheretherketone (PEEK), poly (phthalazinone ether sulfone ketone) (PPESK), polyphenylene sulfide (PPS), polyphenylene ether (PPE), polyphenylene oxide (PPO) and Polyetherimide (PEI). The aromatic hydrophobic segment B may be selected from PSU, PPES, PES, PEEK, PPS, PPE, PPO or PEI, each terminated with one or preferably two amino substituted moieties.
Disclosure of Invention
The applicant believes that there is still a need for membranes that do not release hydrophilic materials when the membranes are used in the biomedical field, more particularly in hemodialysis.
In particular, the applicant noticed that the synthesis disclosed in EP 3108955 in the name of pall corporation cited above requires the use of macromolecular chain transfer agents in order to obtain block copolymers having a predetermined chemical structure. However, although chain transfer agents have been used in free radical polymerization, their use results in a reduction in the rate of polymerization and also results in polymers characterized by low molecular weights, such as weight average molecular weight (M)w) From about 19000 g/mol to about 30000 g/mol (as determined by GPC).
The applicant considered the copolymer disclosed in WO 2013/034611(Gambro Lundia AB), but considered that the low amount of PVP in the final copolymer (2.0 wt.%, based on the total weight of the final copolymer, as shown in example 1) was due to the copolymer being made by a mechanical process.
The applicant has therefore faced the problem of providing a copolymer comprising at least one hydrophobic segment and at least one hydrophilic segment, which is obtainable by chemical synthesis, which is rapid, easy to scale up to industrial plants and does not involve expensive reactants or starting materials.
Furthermore, the applicant faced the problem of providing copolymers having a higher molecular weight than the copolymers already disclosed in the art and comprising covalently bonded PVP, in a weight ratio much higher than 2% (based on the total weight of the final copolymer).
Accordingly, in a first aspect, the present invention relates to a copolymer [ copolymer (P) ] comprising:
-a first segment comprising, preferably consisting of, the repeating unit poly (aryl ether sulfone) [ PAES repeating unit ], and
a second segment comprising, preferably consisting of, the repeating unit poly (vinylpyrrolidone) [ PVP repeating unit ],
wherein the first segment and the second segment are formed by a polymer having the formula-O-Ph-NH-C (═ O) -C (CH)3)2-CH2-are linked together.
Advantageously, the copolymer (P) comprises more than 5 wt.%, preferably more than 10 wt.%, of PVP segments, based on the total weight of the copolymer (P).
Advantageously, the copolymer (P) comprises at least 12 wt.%, even more preferably at least 15 wt.% of PVP segments, based on the total weight of the copolymer (P).
Advantageously, the copolymer (P) is characterized by a weight-average molecular weight (M)w) Is from 50000g/mol to 2000000g/mol (determined by GPC).
In a second aspect, the present invention relates to a process for the synthesis of the above defined copolymer (P), said process comprising the following steps:
(I) providing a poly (aryl ether sulfone) polymer having two chain ends, wherein the two chain ends comprise an amine group [ Polymer (PAES)NN]；
(II) polymerizing said Polymer (PAES)NNReacting with methacryloyl chloride to provide a polymer comprising monomethacrylated PAES [ Polymer (PAES) ]NA]And dimethylacrylated PAES polymers [ polymersNA(PAES)NA]Mixture of [ mixture (M-P1)]；
(III) reacting the mixture (M-P1) obtained in step (II) with a vinylpyrrolidone monomer, thereby providing a mixture comprising polymer (P).
In a third aspect, the present invention relates to a composition [ composition (C) ] comprising:
-at least one polymer (P) as defined above, preferably in an amount of from 0.01 to 30 wt.%, based on the total weight of the composition (C),
-at least one PVP polymer, preferably in an amount of from 1 to 10 wt.%, based on the total weight of the composition (C);
-optionally at least one poly (aryl ether sulfone) (PAES) polymer, preferably in an amount of from 1 to 35 wt.%, based on the total weight of the composition (C); and
-at least one solvent [ medium (L) ], preferably in an amount of more than 60 wt.%, based on the total weight of the composition (C).
In a fourth aspect, the invention relates to a composition comprising at least one porous layer [ layer (L)Q)]Membrane of (film (Q)]Said layer (L)Q) Obtained from composition (C) as defined above.
The applicant has surprisingly found that when a membrane is manufactured using the copolymer (P) according to the invention, said membrane can be used in hemodialysis applications (due to the increased compatibility between the membrane and the blood), while avoiding allergic reactions (due to the PVP not being released in the human body).
Furthermore, the applicant has surprisingly found that using the copolymer of the invention, a membrane is obtained with high blood compatibility, which means that no activation of the blood clotting rate of the patient is detected when using the membrane of the invention.
Thus, in another aspect, the invention relates to a method for the extracorporeal treatment of a body fluid, preferably blood, of a patient, said method comprising the use of at least one membrane (Q) according to the invention.
Detailed Description
For the purposes of this specification and the claims that follow:
the use of parentheses before and after the symbols or numerals identifying the compounds, formulae or parts of formulae has the purpose of better distinguishing only those symbols or numerals from the rest of the text, and therefore said parentheses may also be omitted;
the term "membrane" is intended to mean a discrete, generally thin interface that slows down the permeation of the chemical substance with which it comes into contact, said membrane containing pores of limited size, said pores having the dimensions defined in the following description;
when the membrane of the invention comprises as the only layer a porous layer (L)Q) When used, the term "film (Q)" is used to denote the layer (L)Q) Because the two are coincident;
the term "gravimetric porosity" is intended to mean the fraction of voids with respect to the total volume of the porous membrane;
the term "solvent" is used herein in its usual meaning, i.e. it denotes a substance capable of dissolving another substance (solute) to form a mixture which is uniformly dispersed on a molecular level. In the case of polymeric solutes, the convention refers to solutions of the polymer in a solvent when the resulting mixture is transparent and there is no visible phase separation in the system. The point at which phase separation occurs, commonly referred to as the "cloud point", is believed to be the point at which the solution becomes cloudy or cloudy due to the formation of polymer aggregates;
- "glass transition temperature (T)g) "is intended to mean the temperature as measured by Differential Scanning Calorimetry (DSC) at 20 ℃/min according to ASTM D3418 as detailed in the examples;
the term "porous" is intended to mean that the membrane of the invention contains pores distributed throughout its thickness;
the term "dense" in relation to "film" or "layer" is intended to mean that the film or the layer contains no pores distributed throughout its thickness or, if present, a weight porosity of less than 3%, more preferably less than 1%, based on the total volume of the film;
the expression "as defined above" is intended to include all general and specific or preferred definitions or embodiments mentioned by the expression in the preceding part of the description;
the terms "method" and "method" are synonymous.
As mentioned above, the copolymer (P) according to the invention comprises the repeating unit poly (aryl ether sulfone) [ PAES repeating unit ].
Preferably, said PAES repeat unit is selected from the group comprising, preferably consisting of: polyphenylsulfone (PPSU) repeating units, Polyethersulfone (PES) repeating units, Polyetherethersulfone (PEES) repeating units, and Polysulfone (PSU) repeating units.
For the purposes of the present invention, poly (aryl ether sulfone) (PAES) is intended to mean a polymer comprising at least 50 mol.% of recurring units (R) of formula (K)PAES) Any polymer of (a):
wherein
Each R, equal to or different from each other, is selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, ether, thioether, carboxylic acid, ester, amide, imide, alkali or alkaline earth metal sulfonate, alkyl sulfonate, alkali or alkaline earth metal phosphonate, alkyl phosphonate, amine, and quaternary ammonium;
each h, equal to or different from each other, is an integer ranging from 0 to 4; and
t is selected from the group consisting of: bond, sulfone group [ -S (═ O)2-]And the group-C (R)j)(Rk) -, wherein RjAnd RkIdentical or different from each other, selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, ether, thioether, carboxylic acid, ester, amide, imide, alkali or alkaline earth metal sulfonate, alkyl sulfonate, alkali or alkaline earth metal phosphonate, alkyl phosphonate, amine and quaternary ammonium. RjAnd RkPreferably methyl.
Preferably, at least 60 mol.%, 70 mol.%, 80 mol.%, 90 mol.%, 95 mol.%, 99 mol.%, and most preferably all of the recurring units in the PAES are recurring units (R)PAES)。
In one embodiment, the PAES repeat unit is a polyphenylsulfone (PPSU) repeat unit. As used herein, polyphenylsulfone (PPSU) repeat units are intended to mean polymers comprising greater than 50 mol.% of repeat units having the formula (K' -a):
preferably, at least 60 mol.%, 70 mol.%, 80 mol.%, 90 mol.%, 95 mol.%, 99 mol.%, and most preferably all of the recurring units in the PPSU are recurring units having the formula (K' -a).
In some embodiments, the PAES repeat units are Polyethersulfone (PES) repeat units. As used herein, Polyethersulfone (PES) repeat units are intended to mean any polymer comprising at least 50 mol.% of repeat units having the formula (K' -B):
preferably, at least 60 mol.%, 70 mol.%, 80 mol.%, 90 mol.%, 95 mol.%, 99 mol.%, and most preferably all of the recurring units in the PES are recurring units having the formula (K' -B).
In some embodiments, the PAES repeat unit is a Polysulfone (PSU) repeat unit. As used herein, Polysulfone (PSU) repeat units are intended to mean polymers comprising at least 50 mol.% of repeat units having the formula (K' -C):
preferably, at least 60 mol.%, 70 mol.%, 80 mol.%, 90 mol.%, 95 mol.%, 99 mol.%, and most preferably all of the recurring units in the PSU are recurring units having the formula (K' -C).
According to a preferred embodiment, the PAES repeat units are poly (ether sulfone) (PEES) repeat units. As used herein, poly (ether sulfone) (PEES) repeat units are intended to mean polymers comprising at least 50 mol.% of repeat units having the formula (K' -D):
preferably, at least 60 mol.%, 70 mol.%, 80 mol.%, 90 mol.%, 95 mol.%, 99 mol.%, and most preferably all of the recurring units in the PSU are recurring units having the formula (K' -D).
In addition to the repeating unit having formula (K '-D), the PEES polymer may further comprise a repeating unit having formula (K' -Db):
excellent results have been obtained when the PAES repeat unit is identical to the PSU repeat unit or the PEES repeat unit.
As mentioned above, the copolymer (P) according to the invention comprises the repeating unit poly (vinylpyrrolidone) [ PVP repeating unit ].
The PVP repeat unit preferably conforms to the following formula (I):
wherein o is an integer greater than 1.
Advantageously, said copolymer (P) comprises one segment comprising said PAES repeat unit and one segment comprising said PVP repeat unit, by having the formula-O-Ph-NH-C (═ O) -C (CH)3)2-CH2-are linked together.
Preferably, the copolymer (P) corresponds to the formula:
{E-[PAES]n-O-(C6H4)-NH-C(＝O)-C(CH3)2-CH2}m-[PVP]o-H
wherein
[ PAES ] represents a PAES repeat unit, more preferably a PEES repeat unit, as defined above;
[ PVP ] denotes a PVP repeat unit as defined above;
each of m, n and o, equal to or different from each other, is an integer greater than 1; and is
E is- (C)6H4)-NH-(C＝O)-(C6H5)。
As will be apparent from the following description of the synthesis method of the copolymer (P), the copolymer (P) is provided as a mixture comprising the polymer (P) and a small amount of its corresponding bifunctional polymer, which conforms to the following formula:
E*-{[PAES]n-O-(C6H4)-NH-C(＝O)-C(CH3)2-CH2}m-[PVP]o-H
wherein [ PAES ], [ PVP ], n and o are as defined above, and
e is a group-O- (C)6H4)-NH-C(＝O)-C(CH3)2-CH2-[PVP]o-H。
In step (I) of the process of the invention, the Polymer (PAES) may be prepared using suitable reactants known to those skilled in the artNN。
For example, Polymers (PAES) suitable for step (I) when the polymer (P) comprises recurring units of PPSUNNCan be selected from
PPSU was prepared initially and is commercially available from Solvay Specialty Polymers USA, l.l.c.
When the polymer (P) contains PES repeating units, the Polymer (PAES)NNCan be selected from
PESU (from solvay specialty polymers, llc, usa) starts the preparation.
When the polymer (P) comprises PSU repeating units, the Polymer (PAES)NNCan be selected from
PSU (from solvay specialty polymers llc, usa) was initially prepared.
According to a preferred embodiment, in which the polymer (P) comprises (PEES) recurring units, Polymers (PAES) suitable for step (I)NNCommercially available from Solvay-Cytec Industries under the name KM-177.
In step (II) of the process of the present invention, a radical polymerization is carried out,wherein the Polymer (PAES)NNWith a suitable unsaturated carboxylic acid or acid chloride, such as, for example, methacryloyl chloride, acryloyl chloride, acrylic acid, methacrylic acid, and similar olefin-containing acids, acid chlorides, or derivatives thereof.
Preferably, after step (I) and before step (II), said (PAES)NNThe polymer is advantageously dissolved in a polar aprotic solvent, which is preferably selected from the group consisting of Dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N-butylpyrrolidone (NBP), Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), sulfolane, chloroform, 1, 3-dimethyl-2-imidazolidinone (DMI).
Preferably, step (II) is carried out under heating, more preferably at a temperature from room temperature to 100 ℃.
Preferably, step (II) is carried out in the presence of a polar aprotic solvent, such as those listed above.
Advantageously, when step (II) is carried out under the conditions described above, with said polymerNA(PAES)NAIn contrast, the mixture obtained (M-P1) contained the majority of the Polymer (PAES)NA。
Preferably, the mixture (M-P1) comprises at least 1.01:1, preferably 1.5:1, preferably 2:1, of said Polymer (PAES)NAWith said polymerNA(PAES)NAThe ratio of (a) to (b).
The mixture (M-P1) is advantageously used as such in step (III) of the process according to the invention, since the polymer isNA(PAES)NADoes not adversely affect the reactivity of the subsequent steps. However, if desired, the person skilled in the art can isolate or remove the polymer from the mixture (M-P1) using separation or purification methods known in the artNA(PAES)NA。
Preferably, said step (III) is carried out in the presence of a polar aprotic solvent, such as those listed above.
Preferably, in step (III), the (PAES)NAThe polymer is reacted with PVP in the presence of at least one free radical initiator, more preferably selected from azo compounds, such as azobisisobutyroNitrile (AIBN), or a peroxide, such as benzoyl peroxide or hydroperoxide.
Preferably, step (III) is carried out under heating, more preferably at a temperature between 50 ℃ and 100 ℃.
According to a preferred embodiment, the composition (C) according to the invention comprises at least one polymer (P) as defined above, at least one pore-forming agent and at least one medium (L).
According to this embodiment, the composition (C) preferably comprises:
-from 0.01 to 30 wt.% of at least one polymer (P);
-from 1 to 10 wt.% of at least one pore former; and
-from 65 to 98.99 wt.% of at least one medium (L).
Preferably, the at least one pore former is selected from PVP; polyethylene glycols, polyethylene glycol monoesters and copolymers of polyethylene glycol and polypropylene glycol, such as are known under the trade name BASF AG from BASF AG
Commercially available polymers of F68, F88, F108 and F12; polysorbate esters, such as, for example, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monopalmitate, which are known, for example, under the trade name
And (5) selling.
Preferably, said at least one medium (L) is chosen from water or polar aprotic solvents. More preferably, the polar organic solvent is selected from the group consisting of: n, N-dimethylacetamide (DMAc), N-diethylacetamide, Dimethylformamide (DMF), diethylformamide, NMP, DMI, DMSO, NPB and
Polarclean。
according to another preferred embodiment, the composition (C) according to the invention comprises at least one polymer (P) as defined above, at least one PVP polymer, at least one PAES polymer and at least one medium (L).
According to this embodiment, the composition (C) preferably comprises:
-at least one polymer (P) in an amount of from 0.01 to 10 wt.%, more preferably from 0.5 to 8 wt.%, and even more preferably from 0.9 to 8 wt.%, based on the total weight of the composition (C);
-at least one pore-forming agent in an amount of from 1 to 10 wt.%, based on the total weight of the composition (C);
-at least one PAES polymer in an amount of from 1 to 35 wt.%, more preferably from 5 to 25 wt.%, and even more preferably from 10 to 20 wt.%, based on the total weight of the composition (C); and
-at least one medium (L) in an amount of from more than 60 to 97.99 wt.%, more preferably from 65 to 95 wt.%, and even more preferably from 70 to 90 wt.%, based on the total weight of the composition (C).
Preferably, said PAES polymer is selected from the group comprising, preferably consisting of: polyphenylsulfone (PPSU), Polyethersulfone (PES), Polyetherethersulfone (PEES) and Polysulfone (PSU) as defined above.
Excellent results were obtained when the PEAS polymer was PSU or PES.
According to preferred embodiments, the composition (C) is free of plasticizers, i.e. no plasticizers are added to the composition (C), or they are present in an amount of less than 1 wt.%, more preferably less than 0.1 wt.%, based on the total weight of the composition (C).
A membrane containing pores uniformly distributed throughout its thickness is commonly referred to as a symmetric (or isotropic) membrane; a membrane containing pores that are non-uniformly distributed throughout its thickness is commonly referred to as an asymmetric (or anisotropic) membrane.
The membrane (Q) may be a symmetric membrane or an asymmetric membrane.
Asymmetric membranes (Q) typically comprise an outer layer containing pores having an average pore size that is smaller than the average pore size of the pores in the inner layer or layers. Each of the layers may be a layer (L) as described aboveQ)。
The porous membrane of the present invention preferably has an average pore diameter of less than 100nm, more preferably less than 50nm, and even more preferably less than 10 nm. According to a preferred embodiment, the membrane of the invention suitable for hemodialysis has an average pore size below 8 nm. The average pore size of membranes prepared for use outside hemodialysis is from 0.001 μm to 50 μm.
Suitable techniques for determining the average pore diameter in the porous Membrane of the present invention are described, for example, in Handbook of Industrial Membrane Technology, edited by PORTER, Mark c, Noyes, 1990, pages 70-78. The pore size of the membrane can be estimated by Scanning Electron Microscopy (SEM), and/or measurement of bubble point, gas flux, water flux, and molecular weight cut-off, among other techniques.
The film (Q) typically has a gravimetric porosity comprised between 5% and 90%, preferably between 10% and 85%, more preferably between 30% and 75% by volume, based on the total volume of the film. Good results were obtained with a gravimetric porosity of between 70% and 85% by volume.
Suitable techniques for determining the gravimetric porosity in the membrane (Q) are described, for example, in SMOLDERS, K, et al, microbiology for membrane distillation [ membrane distillation Terminology ]. desalinization [ Desalination ] 1989, Vol.72, p.249-262.
The film (Q) may be a film comprising said layer (L)Q) The self-supporting porous film or multilayer film as the only layer, preferably comprising said layer (L) supported on a substrateQ)。
Said layer (L)Q) May partially or completely extend through the substrate layer.
The substrate is preferably composed of a material that has minimal impact on the selectivity of the porous membrane. The substrate layer is preferably composed of a nonwoven material, glass fibers and/or a polymeric material, such as for example polypropylene, polyethylene terephthalate.
The film (Q) is produced according to a conventional method, for example, a reverse phase method.
In general, for the production of the film (Q), the composition (C) is produced by a conventional method, processed into the film (F), and the film (F) is optionally further processed into the film (Q).
According to a first embodiment, the film (F) and the film (Q) are manufactured by a process [ process (MP-1) ] carried out in liquid phase, which typically comprises:
(i ^) providing the composition (C) as defined above;
(Ii ^) processing the composition (C) provided in step (i ^), thereby providing a film (F); and optionally also (c) a second set of one or more of,
(iii ^) processing the film (F) obtained in step (ii ^) to provide a film (Q).
In step (i ^), composition (C) is produced by any conventional technique. For example, the medium (L) may be added to the copolymer (P) and optionally to the Polymer (PAES) and to any other ingredients, or preferably the Polymer (PAES) and optionally the polymer (P) and any other ingredients are added to the medium (L); alternatively, the Polymer (PAES) and optionally the polymer (P), any other ingredients and the medium (L) are mixed simultaneously.
Any suitable mixing device may be used. Preferably, the mixing equipment is selected to reduce the amount of air entrained in composition (C), which can lead to defects in the final film. Mixing is conveniently carried out in a sealed vessel, optionally maintained under an inert atmosphere. It has been found that an inert atmosphere and more precisely a nitrogen atmosphere is particularly advantageous for the manufacture of composition (C).
In step (i ^) the mixing time required to obtain a clear and homogeneous composition (C) during stirring can vary widely depending on the dissolution rate of the components, the temperature, the efficiency of the mixing device, the viscosity of the composition (C), and the like.
In step (ii ^) composition (C) is typically processed in the liquid phase.
In step (ii ^) composition (C) is processed, typically by casting, to provide film (F).
Casting generally involves solution casting, wherein a liquid composition comprising a suitable medium (L) is spread into a uniform film on a suitable support, typically using a casting knife, a stretching rod or a slot die.
In step (ii ^) the temperature at which composition (C) is processed by casting may be the same as or may be different from the temperature at which composition (C) is mixed with stirring.
Different casting techniques are used depending on the final form of the film (Q).
When the film (Q) is a flat film, the composition (C) is cast as a thin film (F) on a flat support substrate (typically a floor, belt or fabric) or another microporous support film, typically by means of a casting knife, a stretching bar or a slit die.
According to a first embodiment of step (ii ^) composition (C) is processed by casting onto a flat support substrate to provide a flat film (F).
According to a second embodiment of step (ii ^) composition (C) is processed by casting to provide tubular film (F).
According to a variant of this second embodiment of the invention, a spinneret is used to produce the tubular film (F).
The term "spinneret" is hereby understood to mean an annular nozzle comprising at least two concentric capillaries: a first external capillary for the passage of the composition (C), and a second internal capillary for the passage of a supporting fluid (generally known as "flow"). Optionally, the coating may be extruded using an external capillary.
Hollow fibers and capillary membranes can be manufactured according to this variant of the second embodiment of step (ii ^) by a so-called spinning process. According to this variant, composition (C) is generally pumped through a spinneret; the flow acts as a support for the cast composition (C) and keeps the hollow fiber or capillary precursor holes (bore) open. The stream may be a gas, or preferably a medium (NS) or a mixture of a medium (NS) and a medium (L). The choice of the flow and its temperature depends on the desired properties of the final membrane, as they may have a significant effect on the size and distribution of the pores in the membrane.
At the outlet of the spinneret, after a short residence time in air or in a controlled atmosphere, the hollow fibers or capillary precursors are precipitated in step (iii ^) of (MP-1), providing a hollow fiber or capillary membrane (Q).
The supporting fluid forms the pores of the final hollow fiber or capillary membrane (Q).
Tubular membranes, due to their large diameter, are typically manufactured using a different process than that used to produce hollow fiber membranes.
The temperature gradient between the film and the medium (NS) provided in either of steps (ii ^) and (iii ^) of method (MP-1) should be chosen by the person skilled in the art in such a way as to regulate the rate of precipitation of the (PAES) polymer from composition (C).
Thus, a first variant of method (MP-1) comprises:
(i ^) providing the composition (C) as defined above;
(ii ^ processes the composition (C) provided in step (i ^) to provide a film; and optionally (iii ^) contacting the thin film provided in step (ii ^) with a non-solvent medium [ medium (NS) ] to provide a film (Q).
Another variant of [ method (MP-1) ] comprises:
(i ^ providing composition (C) as defined above;
(ii ^ processes composition (C) provided in step (i ^ to) to provide a film; and optionally
(iii ^ by cooling processes the thin film provided in step (ii ^ by), thereby providing porous film (Q).
In step (ii ^ at), the film is typically processed at a temperature high enough to maintain composition (C) as a homogeneous solution.
In step (ii ^ a), the film is typically processed at a temperature comprised between 60 ℃ and 250 ℃, preferably between 70 ℃ and 220 ℃, more preferably between 80 ℃ and 200 ℃.
In step (iii ^ by), the film provided in step (ii ^ by) is treated by cooling to a temperature of less than 100 ℃, preferably less than 60 ℃, more preferably less than 40 ℃, typically using any conventional technique.
In step (iii ^ a), cooling is typically performed by contacting the thin film provided in step (ii) with a liquid medium [ medium (L') ].
In step (iii ^ x), medium (L') preferably comprises water and more preferably consists of water.
Alternatively, in step (iii ^ the cooling is performed by contacting the film provided in step (ii ^ the) with air.
In step (iii ^ a), the medium (L') or the air is typically kept at a temperature lower than 100 ℃, preferably lower than 60 ℃, more preferably lower than 40 ℃.
Another variant of method (MP-1) comprises:
(i ^ x) providing composition (C) as defined above;
(ii ^ processing the composition (C) provided in step (i ^ to provide a film (F); and optionally
(iii ^ by absorbing the non-solvent medium [ medium (NS) ] from the vapor phase processes the thin film (F) provided in step (ii ^ by), thereby providing the porous film (Q).
In step (iii ^ x), the thin film (F) provided in step (ii ^ x) is preferably precipitated by absorbing water from the water vapor phase.
In step (iii ^ x), the film (F) provided in step (ii ^ x) is preferably precipitated in air, typically having a relative humidity greater than 10%, preferably greater than 50%.
Variants of [ method (MP-1) ] include:
(i ^ x) providing composition (C) as defined above;
(ii ^ processing the composition (C) provided in step (i ^ to provide a film (F); and optionally
(iii ^ through process the membrane that provides in step (ii ^ through evaporation medium (L)) to provide porous membrane (Q).
Preferably, when medium (L) comprises more than one organic solvent, step (ii ^ comprises processing composition (C) to provide a film, and then precipitating the film in step (iii ^ by evaporating medium (L) at a temperature above the boiling point of the organic solvent having the lowest boiling point.
According to a preferred embodiment, step (ii) is carried out by processing composition (C) with a high voltage electric field.
The method (MP-1) may be comprised in one or more of the variants previously described herein.
The film (Q) obtainable by the process (MP-1) may be subjected to additional post-treatment steps, such as rinsing and/or stretching and/or heat treatment (annealing).
The membrane (Q) obtainable by process (MP-1) is typically flushed with a liquid medium which is miscible with medium (L).
The film (Q) obtainable by (MP-1) may advantageously be stretched to increase its average porosity.
Depending on the end intended use of the membrane, the membrane (Q) may be flat when a flat membrane is desired, or tubular or hollow fiber membrane in shape when a tubular or hollow fiber membrane is desired.
When the film (Q) is flat, its thickness is advantageously from about 10 to about 300 microns, more preferably from about 25 to about 150 microns.
When the membrane (Q) is tubular, its outer diameter may be up to 10 mm.
When the membrane (Q) has an outer diameter comprised between 0.5mm and 3mm, it is called a hollow fiber membrane. When the membrane (Q) has a diameter of less than 0.5mm, it is called a capillary membrane.
The membranes (F) and (Q) according to the invention can be used in a number of technical fields, in particular for filtration and reverse osmosis of liquid and/or gas phases (as thin, selectively dense layers).
Accordingly, in one aspect, the present invention relates to the use of a membrane (Q) for filtering a liquid and/or gas phase comprising one or more solid contaminants.
In another aspect, the present invention relates to a method for filtering a liquid and/or gas phase comprising one or more solid contaminants, said method comprising contacting said liquid and/or gas phase comprising one or more solid contaminants with a membrane (Q) of the present invention.
The liquid and gaseous phases containing one or more solid contaminants are also referred to as "suspensions", i.e. homogeneous mixtures comprising at least one solid particle (contaminant) dispersed into a continuous phase (or "dispersion medium" in liquid or gaseous form).
Said at least one solid contaminant preferably comprises microorganisms, preferably selected from the group consisting of: bacteria such as Staphylococcus aureus (Staphylococcus aureus) and Pseudomonas aeruginosa (Pseudomonas aeruginosa), algae, fungi, protozoa, and viruses.
The membrane (Q) may be used for filtering biological solutions (e.g. bioburden, viruses, other macromolecules) and/or buffer solutions (e.g. solutions that may contain small amounts of solvents like DMSO or other polar aprotic solvents).
In one embodiment, two or more porous membranes (Q) may be used in series for filtration of the liquid and/or gas phase. Advantageously, the first filtration step is carried out by: contacting the liquid and/or gaseous phase comprising the solid contaminant(s) with a membrane (Q) according to the invention having an average pore size of more than 5 μm, more preferably from 5 μm to 50 μm; and after the first filtration step a second filtration step is performed by: the same liquid and/or gas phase is brought into contact with a membrane (Q) having an average pore diameter of from 0.001 to 5 μm.
Alternatively, at least one membrane (Q) is used in series with at least one porous membrane obtained from a composition different from composition (C) according to the invention.
According to a particular and further embodiment of the invention, the membrane (Q) in the form of a tubular or hollow fiber and having a mean pore size of from 0.001 to 5 μm is used in an extracorporeal blood circuit or dialysis filter to purify biological fluids, i.e. blood. It has indeed been observed that the membrane (Q) according to the invention is antithrombotic; in particular, it has been observed that the membrane (Q) comprising the copolymer (P) of the invention has an antithrombotic effect.
The term "antithrombotic" as used herein means that the rate of thrombosis when whole blood is in contact with the membrane (Q) is lower than the rate of thrombosis when whole blood is in contact with a membrane prepared starting from a composition not comprising copolymer (P). In the art, it is well known, for example from US 2015/0008179 (interfacial biologies company), that anticoagulants, such as heparin, are typically added to prevent clotting or thrombosis as blood is transported into and out of the body of a patient undergoing hemodialysis. However, if on the one hand the use of heparin is advantageous, it may be complicated by allergic reactions and bleeding and, in addition, it is contraindicated in patients taking certain drugs.
Thus, in another aspect, the invention relates to the use of a membrane (Q) in the form of hollow fibers having a mean pore size of from 1nm to 16nm as a component in an extracorporeal blood circuit or dialysis filter.
In another aspect, the invention relates to a method for treating a subject suffering from impaired renal function, the method comprising subjecting the patient to a procedure selected from hemodialysis, hemofiltration, hemoconcentration or hemodiafiltration, said procedure being carried out using a dialysis filter comprising at least one membrane (Q) in the form of a tubular or hollow fiber having a mean pore size from 1 to 16 nm.
In another aspect, the invention relates to a method for purifying a blood product, such as whole blood, plasma, fractionated blood components or mixtures thereof, wherein the method comprises dialyzing said blood product across at least one hollow fiber membrane having a mean pore size of from 0.001 to 5 μm and comprising at least one layer (L) as defined aboveQ)。
If the disclosure of any patent, patent application, and publication incorporated by reference conflicts with the present description to the extent that the statements may cause unclear terminology, the present description shall take precedence.
The invention will be explained in more detail below with the aid of examples contained in the experimental section below; these examples are merely illustrative and are in no way to be construed as limiting the scope of the invention.
Experimental part
Material
The following are available from Sigma-Aldrich (Sigma-Aldrich) usa:
dimethylacetamide (DMAc), chlorobenzene (MCB), Azobisisobutyronitrile (AIBN), vinyl pyrrolidone monomer, methacryloyl chloride, tributylamine, polyvinylpyrrolidone (PVP) K90, and Isopropanol (IPA).
Amine-terminated PEES polymers (KM-177),
3000MP Polyethersulfone (PESU) and
3500LCD MB3(PSU) was obtained from Solvay specialty polymers, Inc., USA.
Method
GPC-molecular weight (Mn, Mw)
Viscotek GPC Max (autosampler, pump and degasser) with TDA302 triple detector array consisting of RALS (right angle light scattering), RI and viscosity meter was used.
The sample was run through a set of 3 columns at 1.0mL/min in NMP containing 0.2 w/w% LiBr at 65 ℃: guard column (CLM 1019-with 20k Da exclusion limit), high Mw column (CLM1013, excluding 10MM daltons with respect to polystyrene) and low Mw column (CLM 1011-with 20k daltons exclusion limit with respect to PS).
Calibration was done using a single monodisperse polystyrene standard of about 100k Da.
The light scattering, RI and viscosity detectors are calibrated based on a set of input data provided according to a standard.
Samples of about 2mg/mL in NMP/LiBr were prepared.
Viscotek's OMNISec v4.6.1 software was used for data analysis.
Thermogravimetric analysis (TGA)
TGA experiments were performed using TGA Q500 from TA instruments (TA Instrument). TGA measurements were obtained by heating the sample from 20 ℃ to 800 ℃ under nitrogen at a heating rate of 10 ℃/min.
1H NMR
Measurement with TCE as deuterated solvent using 400MHz Bruker spectrometer1H NMR spectrum. All spectra were referenced to residual protons in the solvent.
DSC
DSC for measuring glass transition temperature (T)g)。
DSC experiments were performed using Q100 from TA instruments. The DSC curve was recorded by heating the sample between 25 ℃ and 320 ℃ at a heating and cooling rate of 20 ℃/min, cooling, reheating and then re-cooling. All DSC measurements were taken under a nitrogen purge.
Unless otherwise indicated, the reported T is provided using the second heating profilegThe value is obtained.
Contact angle
The static contact angle of water at 25 ℃ was evaluated according to ASTM D5725-99 by using a DSA10 instrument (from Kruss, Inc., Germany).
Measurements were made on the upper side (interface with air) of the membrane and dense film. These values are the average of at least 6 measurements.
Gravimetric porosity measurement
The gravimetric porosity of a membrane is defined as the volume of pores divided by the total volume of the membrane.
The film porosity (. epsilon.) was determined according to the gravimetric method as detailed below.
The fully dried film was weighed and immersed in Isopropanol (IPA) for 24 h. After this time, excess liquid was removed with tissue paper (tissue paper) and the film weight was measured again. Porosity was measured according to the procedure described in the following using IPA (isopropyl alcohol) as the wetting fluid: appendix of Desalination 72(1989) 249-262.
Wherein
"wet" is the weight of the wet film,
dry is the weight of the dry film,
ρpolymer and method of making sameIs the density of PSU (1.30 g/cm)3) And is and
ρliquid, method for producing the same and use thereofIs the density of IPA (0.78 g/cm)3)。
Tensile measurement
The mechanical properties of the flat sheet porous film were evaluated at room temperature (23 ℃) according to the ASTM D638 standard procedure (type V, holding distance 25.4mm, initial length Lo 21.5 mm). The speed is between 1 and 50 mm/min. The flat sheet porous membrane stored in water was removed from the container box and immediately tested.
Water absorption
The water absorption test was performed according to ASTM D570 ("standard test method for plastic absorption") on dense, non-porous films. Samples (each about 2X 3 cm)2) Dried in a vacuum oven at 105 ℃ for 24h, then cooled in a desiccator and weighed immediately to the nearest 0.001 g. They were then placed in a container of distilled water maintained at a temperature of 23 + -1 deg.C. After soaking for 48h, they were removed from the water once, wiped off all surfaces with a dry cloth, and weighed immediately to the nearest 0.001 g. The values quoted are the average of at least 6 articles per polymer type.
Synthesis of
Step (a): synthesis of methacryloylated polyether ether sulfones
The reaction takes place in a glass reactor vessel (1L) equipped with an overhead stirrer, nitrogen inlet and overhead distillation. KM-177(600g) was dried under vacuum at 110 ℃ overnight and then charged into the reactor. Next, dimethylacetamide (900g) was added to dissolve the polymer. Tributylamine (132g) and chlorobenzene (300g) were added to the polymer solution.
The reaction mixture was heated from room temperature to 170 ℃ using a1 ℃/min heating ramp so that most of the chlorobenzene was distilled off. The heating was decreased to bring the internal temperature to 60 ℃ and methacryloyl chloride was added dropwise over a period of 30 minutes. The reaction was allowed to proceed at 60 ℃ for 12 hours. Then, benzoyl chloride (10.11g) was added, and the reaction was further carried out for 4 hours.
After completion of the reaction, the reaction mixture was condensed in methanol (3L) and washed with hot water, and then dried in a vacuum oven at 110 ℃ overnight.
And (3) characterization:
GPC：Mn＝21035g/mol，Mw＝10158g/mol，PDI＝2.07
TGA: onset of thermal degradation was observed at 500 ℃.
DSC: observed at 199 ℃ to correspond to TgThermal transformation of (2).
1H-NMR (d-TCE solvent): the presence of methacryloyl groups was confirmed by the appearance of 2.08ppm of methyl singlet and of two singlet states of olefinic protons at 5.5ppm and 5.8ppm, which were not present in the polymer before the reaction.
Step (b): copolymerization of methacryloylated polyether ether sulfones
The reaction takes place in a glass reactor vessel (1L) equipped with an overhead stirrer, nitrogen inlet and overhead distillation. The methacrylated Polyethersulfone (PEES) (150g) obtained in step (a) was dried under vacuum at 110 ℃ overnight and then charged into the reactor. Then, dimethylacetamide (1500g) was added and the polymer was dissolved. To the polymer solution was added vinyl pyrrolidone (200.25g) and the solution was purified by purging N at room temperature2The solution was degassed for 30 minutes.
AIBN was then added to the reaction mixture and the reaction temperature was raised to 60 ℃ for 2 hours, then to a temperature of 75 ℃ for 24 hours.
The reaction mixture was then coagulated in water and the coagulated material was washed with 300g of boiling water for 1 hour. This was repeated five times, each time using a fresh water wash to ensure that any free PVP polymer was washed away. After the fifth water wash, the polymer was dried under vacuum at 100 ℃ overnight.
And (3) characterization:
light scattering GPC: mn＝373042g/mol，Mw＝1321000g/mol，PDI＝3.54
TGA: TGA shows two different thermal degradation temperatures: onset of thermal degradation at 379 ℃ indicates thermal degradation of PVP, and another thermal degradation at 520 ℃ indicates PEES degradation.
DSC: a single T was observed at 207 ℃g。
1H NMR: methacryloyl olefinic protons disappear completely and the aliphatic region appears broad, characteristic of polyvinylpyrrolidone being visible.
Contact angle: the contact angle of the polymer cast film was 66 ° lower than typical PEES polymer, indicating a more hydrophilic surface compared to unmodified PEES polymer.
General procedure for preparing a solution of copolymer (P) for the manufacture of porous or dense films
The solution is prepared by mixing the selected polymer (PSU or PESU) and/or copolymer (P) obtained at the end of step (b) above in a glass bottle by magnetic stirring. DMAc and optionally a pore former (PVP K90) are added and stirring is carried out at a temperature ranging from 25 ℃ to 80 ℃ for a time ranging from 30 minutes to 6 hours.
Solutions having the compositions provided in table 1 below were prepared.
TABLE 1
Comparative
Preparation of dense films
Flat sheet films were prepared by film forming the polymer solution obtained according to the procedure disclosed above on a suitable smooth glass support at 40 ℃ by means of an automated casting knife. The knife gap was set to 500 μm. After casting, the solvent was evaporated in a vacuum oven at 130 ℃ for several hours.
Dense films were prepared starting from sample numbers 1, 5 and 6 (. sup.), and the mechanical properties of the dense films were evaluated. The results are reported in table 2 below:
TABLE 2
Comparative
Preparation of porous membranes
Flat sheet porous membranes were prepared by forming the solution into a thin film on a suitable smooth glass support with the aid of an automated casting knife.
Film casting is performed by maintaining the dope solution, the casting blade and the support at a temperature of 25 ℃ to prevent premature precipitation of the polymer. The knife gap was set to 250 μm.
Immediately after casting, the thin film of the apertured film was immersed in a coagulating bath to cause phase inversion. The coagulation bath consisted of pure deionized water or mixed water/DMAC 50/50 v/v. After coagulation, the membranes were washed several times in pure water over the following several days to remove residual traces of solvent. The membrane (wet) was stored in water.
Porous membranes were prepared starting from solution sample No. 1 and solution sample No. 4, with PVP K90 added in the amounts detailed in table 3 below. The properties of the coagulation bath and the film are also detailed in table 3:
TABLE 3
The covalent bond between PVP and PESU or PSU polymers was confirmed by NMR analysis of dense and porous films as shown in table 4 below:
TABLE 4
Blood coagulation test (determination of the time of the unactivated partial thromboplastin-uPTT)
According to ISO 10993-4:2017[ biocompatibility test-Biological evaluation of medical devices-Part 4: Selection of tests for interventions with blood ] [ blood compatibility test-Biological evaluation of medical devices-Part 4: test selection for interaction with blood ] partial thromboplastin time (uPTT) was assessed for plasma in contact with a non-porous dense membrane (in duplicate). The test was performed using plasma from patients who were randomly selected and not receiving anticoagulation therapy.
Will be 12cm2(6+6cm2) The non-porous dense film sample of (2) was immersed in 2ml of plasma to reach a surface/volume ratio of 6cm2/ml and incubated under dynamic conditions (stirrer) at a temperature of 37 ℃. + -. 1 ℃ for 30 minutes.
Blood assays were performed on control plasma that was not contacted with the test article and test plasma that was contacted with the test article. Clotting time values were calculated as a percentage of negative control using the following equation:
D＝[(T-C)/T]x 100
wherein:
d-difference between treatment and control (%)
Time value of the average uPTT of the treated plasma, i.e. the plasma exposed to the article (in seconds; repeated twice)
C-the mean ptt time value for control plasma (in seconds; repeated twice).
The results are reported in table 5 below.
Platelet aggregation assay
The purpose of the biological assessment is to obtain the necessary data to assess whether the sample interacts with whole blood to induce platelet aggregation.
The tests were carried out according to ISO 10993-4: 2017. The haemocompatibility test was performed using blood from a donor who was randomly selected and not receiving anticoagulation treatment.
12cm2(6+6 cm)2) The test sample(s) was immersed in 2ml of plasma to reach a surface/volume ratio of 6cm2/ml and incubated under dynamic conditions (stirrer) at a temperature of 37 ℃. + -. 1 ℃ for 30 minutes.
The control blood assay was performed on the remaining portion of the lithium-heparin blood fraction that was not contacted with the test article.
The platelet aggregation test assesses the ability of platelets to adhere to each other. Platelets are activated by the activator TRAP-6 (thrombin receptor activating peptide 6) and pass through two electrodes immersed in the blood. This test measures the change in electrical impedance that occurs when platelets aggregate.
The results are expressed as the rate of aggregation over time and the area under the curve (AUC) is measured (two independent determinations performed simultaneously in the same tube). If contact with the test article results in platelet aggregation, a decrease in this parameter is detected.
The result "area under the curve" (AUC) is expressed in AU/min (absorbance units) and is the average between two independent and simultaneous measurements performed on the same tube.
The values are expressed as:
D＝[(T-C)/T]x 100
wherein:
d-difference between treatment and control (%)
T ═ treated sample (AUC, blood exposed to sample)
Control AUC (AUC, control blood not contacted with sample)
A positive value indicates that there was no aggregation at all (i.e., better than control blood that was not exposed to the sample).
The results are reported in table 5 below.
TABLE 5
Comparative
The above results show that the addition of polymer P reduces the coagulation tendency of the blood, making the composition of the invention superior to the two control samples in the preparation of membranes for hemodialysis.
Claims (15)
1. A copolymer [ copolymer (P) ] comprising:
-a first segment comprising, preferably consisting of, the repeating unit poly (aryl ether sulfone) [ PAES repeating unit ], and
a second segment comprising, preferably consisting of, the repeating unit poly (vinylpyrrolidone) [ PVP repeating unit ],
wherein the first segment and the second segment are formed by a polymer having the formula-O-Ph-NH-C (═ O) -C (CH)3)2-CH2-are linked together.
2. The copolymerization of claim 1(iii) a compound (P), wherein the copolymer (P) comprises more than 5 wt.%, preferably more than 10 wt.% of PVP repeating units and/or has a weight average molecular weight (M) of from 50000 to 2000000g/mol, based on the total weight of the copolymer (P)w) (measured by GPC).
3. Copolymer (P) according to claim 1 or 2, wherein the PVP repeat unit preferably conforms to the following formula (I):
wherein o is an integer greater than 1.
4. The copolymer (P) according to claim 1, wherein the PAES repeat units comprise at least 50 mol.% of repeat units (R) of formula (K)PAES)：
Wherein
Each R, equal to or different from each other, is selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, ether, thioether, carboxylic acid, ester, amide, imide, alkali or alkaline earth metal sulfonate, alkyl sulfonate, alkali or alkaline earth metal phosphonate, alkyl phosphonate, amine, and quaternary ammonium;
each h, equal to or different from each other, is an integer ranging from 0 to 4; and is
T is selected from the group consisting of: bond, sulfone group [ -S (═ O)2-]And the group-C (R)j)(Rk) -, wherein RjAnd RkIdentical or different from each other, selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, ether, thioether, carboxylic acid, ester, amide, imide, alkali or alkaline earth metal sulfonate, alkyl sulfonate, alkali or alkaline earth metal phosphonate, alkyl phosphonate, amine and quaternary ammonium; rjAnd RkPreferably methyl.
5. The copolymer (P) according to claim 4, wherein said PAES recurring units are selected from the group comprising, preferably consisting of:
-a Polysulfone (PSU) repeat unit comprising at least 50 mol.% of a repeat unit having the formula (K' -C):
-polyphenylsulfone (PPSU) recurring units comprising more than 50 mol.% of recurring units of formula (K' -a):
-Polyethersulfone (PES) recurring units comprising at least 50 mol.% of recurring units having the formula (K' -B):
-poly (ether sulfone) (PEES) recurring units comprising at least 50 mol.% of recurring units of formula (K' -D):
optionally a repeat unit of formula (K' -Db):
6. a process for the synthesis of a copolymer (P) as defined in any one of claims 1 to 5, comprising the steps of:
(I) providing a poly (aryl ether sulfone) polymer having two chain ends, wherein the two chain ends comprise an amine group [ Polymer (PAES)NN]；
(II) polymerizing said Polymer (PAES)NNReacting with methacryloyl chloride to provide a polymer comprising monomethacrylated PAES [ Polymer (PAES) ]NA]And dimethylacrylated PAES polymers [ polymersNA(PAES)NA]Mixture of [ mixture (M-P1)]；
(III) reacting the mixture (M-P1) obtained in step (II) with a vinylpyrrolidone monomer, thereby providing a mixture comprising polymer (P).
7. The method of claim 6, wherein step (II) is performed
-by making the Polymer (PAES)NNReacting with unsaturated acid or acyl chloride; and/or
Under heating, more preferably at a temperature of up to 100 ℃; and/or
-in the presence of a polar aprotic solvent.
8. The method of claim 6, wherein the polymer is polymerized withNA(PAES)NAIn contrast, the mixture (M-P1) comprises a majority of the Polymer (PAES)NAPreferably, said Polymer (PAES)NAWith said polymerNA(PAES)NAIs at least 1.01:1, more preferably 1.5: 1.
9. The method of claim 6, wherein step (III) is performed
-in the presence of a polar aprotic solvent; and/or
-in the presence of at least one radical initiator, preferably chosen from azo compounds or peroxides; and/or
Under heating, more preferably at a temperature between 50 ℃ and 100 ℃.
10. A composition [ composition (C) ] comprising:
-at least one copolymer (P) as defined in any one of claims 1 to 5, preferably in an amount of from 0.01 to 30 wt.%;
-at least one pore-forming agent, preferably in an amount of from 1 to 10 wt.%; and
-at least one medium (L), preferably in an amount of more than 60 wt.%,
these amounts are based on the total weight of the composition (C).
11. Composition (C) according to claim 10, further comprising at least one poly (aryl ether sulfone) (PAES) polymer, preferably in an amount of from 1 to 35 wt.%, based on the total weight of the composition (C).
12. Membrane [ membrane Q]Comprising at least one porous layer [ layer (L) ]Q)]Said layer (L)Q) Obtained from a composition (C) as defined in claim 10 or claim 11.
13. A method for the extracorporeal treatment of a body fluid, preferably blood, of a patient, the method comprising the use of at least one membrane (Q) according to claim 12.
14. A method for treating a subject suffering from impaired renal function, said method comprising subjecting the patient to a procedure selected from hemodialysis, hemofiltration, hemoconcentration or hemodiafiltration, said procedure being performed using a dialysis filter comprising at least one membrane (Q) as defined in claim 12, said membrane being in the form of a tube or hollow fiber having a mean pore size from 1nm to 16 nm.
15. A method for purifying a blood product, such as whole blood, plasma, fractionated blood components or mixtures thereof, wherein said method comprises dialyzing said blood product through at least one membrane (Q) as defined in claim 12, said membrane (Q) being in the form of hollow fibers having a mean pore size of from 0.001 to 5 μ ι η.
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| US201962883269P | 2019-08-06 | 2019-08-06 | |
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| EP19197990.5 | 2019-09-18 | ||
| EP19197990 | 2019-09-18 | ||
| PCT/EP2020/071807 WO2021023711A1 (en) | 2019-08-06 | 2020-08-03 | Membrane and polymer for the manufacture thereof |
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| EP (1) | EP4010427A1 (en) |
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Citations (5)
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|---|---|---|---|---|
| WO2000074877A1 (en) * | 1999-06-07 | 2000-12-14 | Nicast Ltd. | Filtering material and device and method of its manufacture |
| US20110240550A1 (en) * | 2010-03-31 | 2011-10-06 | General Electric Company | Block copolymer membranes and associated methods for making the same |
| WO2015075178A1 (en) * | 2013-11-22 | 2015-05-28 | Basf Se | Polymeric antifouling additives for membranes |
| DE102014018481A1 (en) * | 2014-12-16 | 2015-10-29 | Mann + Hummel Gmbh | Ceramic filter membrane and filter module |
| EP3108955A1 (en) * | 2015-06-25 | 2016-12-28 | Pall Corporation | Self-wetting porous membranes |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| SE460521B (en) | 1987-08-31 | 1989-10-23 | Gambro Dialysatoren | PERMSELECTIVE ASYMMETRIC MEMBRANE AND PROCEDURES FOR ITS PREPARATION |
| CN102553441B (en) | 2006-10-18 | 2016-04-13 | 甘布罗伦迪亚股份有限公司 | Micro-dialysis device |
| EP2113298B1 (en) | 2008-04-30 | 2013-04-24 | Gambro Lundia AB | Hollow fibre membrane for hemodialysis with improved permeability and selectivity |
| PT2295132T (en) | 2009-05-15 | 2016-11-15 | Interface Biologics Inc | Antithrombogenic hollow fiber membranes, potting material and blood tubing |
| ATE532577T1 (en) | 2009-05-20 | 2011-11-15 | Gambro Lundia Ab | MEMBRANES WITH IMPROVED PERFORMANCE |
| EP2567750B1 (en) | 2011-09-08 | 2014-12-24 | Gambro Lundia AB | Hollow fiber membrane |
| US10239023B2 (en) * | 2015-06-25 | 2019-03-26 | Pall Corporation | Self-wetting porous membranes (II) |
-
2020
- 2020-08-03 EP EP20746685.5A patent/EP4010427A1/en active Pending
- 2020-08-03 WO PCT/EP2020/071807 patent/WO2021023711A1/en unknown
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000074877A1 (en) * | 1999-06-07 | 2000-12-14 | Nicast Ltd. | Filtering material and device and method of its manufacture |
| US20110240550A1 (en) * | 2010-03-31 | 2011-10-06 | General Electric Company | Block copolymer membranes and associated methods for making the same |
| WO2015075178A1 (en) * | 2013-11-22 | 2015-05-28 | Basf Se | Polymeric antifouling additives for membranes |
| DE102014018481A1 (en) * | 2014-12-16 | 2015-10-29 | Mann + Hummel Gmbh | Ceramic filter membrane and filter module |
| EP3108955A1 (en) * | 2015-06-25 | 2016-12-28 | Pall Corporation | Self-wetting porous membranes |
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| US20220267497A1 (en) | 2022-08-25 |
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